The present invention refers to new compounds having the general formula (I): 
in which:
X1, X2, X3, X4, which may be the same or different from one another, represent a group chosen from among xe2x80x94CONRxe2x80x94, xe2x80x94NRCOxe2x80x94, xe2x80x94OCOxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94CH2NRxe2x80x94, xe2x80x94NRxe2x80x94CH2xe2x80x94, CH2xe2x80x94CH2, where R is H or a C1-3 alkyl or benzyl;
f, g, h, m, which may be the same or different from one another, represent a number chosen from among 0, 1 or 2;
R1 and R2, which may be the same or different from one another, represent a xe2x80x94(CH2)rxe2x80x94Ar group, where r=0, 1, 2 and where Ar is an aromatic group chosen from among: benzene, naphthalene, thiophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, and benzo-imidazole, the said Ar group being possibly substituted with a maximum of 2 residues chosen from among C1-3 alkyl or halo-alkyl, C1-3 alkoxyl, C2-4 amino-alkoxyl, halogen, OH, NH2, NR13R14 where R13 and R14, which may be the same or different from one another, represent hydrogen or C1-3 alkyl;
R3 represents a group chosen from among:
hydrogen
linear or branched alkyl having the formula CnH2n+1, with n=1-5, cyclo-alkyl or alkylcyclo-alkyl groups having the formula CnH2nxe2x88x921 with n=5-9
(CH2)rxe2x80x94Ar1, where r=0, 1, 2 and where Ar1 is an aromatic group chosen from among: benzene, naphthalene, thlophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, and benzo-imidazole, the said Ar1 group being possibly substituted with a maximum of 2 residues chosen from among C1-3 alkyl or halo-alkyl, C1-3 alkoxyl or amino-alkoxyl, halogen, OH, NH2, NR13R14, where R13 and R14, which may be the same or different from one another, represent hydrogen or C1-3 alkyl;
R4 represents a group chosen from among:
hydrogen or C1-6 alkyl
L-Q, where L is a chemical bond or a linear or branched C1-6 alkyl residue and Q is a group chosen from among:
i) H, OH, OR9, NH2, NR9R10, guanidine, sulphate, phosphonate, phosphate, where R9 and R10, which may be the same or different from one another, represent a hydrogen, C1-3 alkyl group, C1-3hydroxyalkyl, C1-3dihydroxyalkyl, C1-3alkyl-CONHR12, C1-3alkyltetrazole, C1-3alkyl-COOH or wherein R9R10 joined together form with the N-atom a saturated 4-6 membered heterocycle possibly containing a further heteroatom chosen in the group consisting of N, O, S and wherein R12 is a mono-, di-, tri-glycosidic group possibly protected with one or more C1-3-acyl groups or substituted with amino-groups or C1-3acylamino-groups;
ii) COOH, tetrazole, SO2NH2, SO2NHCOOR8, CONHR8, NHCOR8, where R8 represents a linear or cyclic C1-6 alkyl chain containing one or more polar groups chosen from among the group: OH, NH2, NR15R16, COOH, CONHR12, PO3H, SO3H, OR11 and where R15 and R16, which may be the same or different from one another, represent a hydrogen or C1-3 alkyl group, and where R11 is a C1-3 alkyl or C2-4 amino-alkyl chain, R12 is a mono-, di-, tri-glycosidic group possibly protected with one or more C1-3acyl groups or substituted with amino-groups or C1-3acylamino-groups or R15R16 joined together form with the N-atom a saturated 4-6 membered heterocycle possibly substituted with C1-3alkyl-groups or with saturated 4-6 membered heterocycle-groups containing at least an N-atom;
iii) COOR17, CONHR12, OR12 where R12 is a mono-, di- or tri-glycoside group possibly protected with one or more C1-3 acyl groups or substituted with amine or C1-3 acylamine groups and R17 is a group R12 as above definined or a group C1-3alkyl, C1-3alkylphenyl, wherein the phenyl-group can be substituted with a group OH, NO2, NH2, CN, CH3, Cl, Br;
R5, R6, R7, which may be the same or different from one another, represent a hydrogen or C1-3 alkyl group; with the proviso that when R1 and R2 are benzyl or 4-hydroxybenzyl then R3 and R4 are not isopropyl.
Also included in the present invention are the pharmaceutically acceptable salts, the processes for their preparation, and the pharmaceutical compositions containing them.
In view of the presence of chiral centres in the compounds of formula (I), also the individual enantiomers and their mixtures, both in the racemic form and in the non-racemic form, form part of the present invention.
The NK-2 receptor of tachykinins is widely expressed in the peripheral nervous system of mammals. One of the various effects produced by the selective stimulation of the NK-2 receptor is the contraction of smooth muscle. Hence antagonists of the NK-2 receptor may be considered agents capable of controlling excessive contraction of smooth muscle in any pathological condition in which the release of tachykinins concurs in the genesis of the corresponding disorder.
In particular, the bronchospastic and inflammatory component of asthma, coughing, pulmonary irritation, intestinal spasms, spasms of the biliary tract, local spasms of the bladder and of the ureter during cystitis, kidney infections and colics may be considered conditions in which the administration of NK-2 antagonists may be effective (E. M. Kudlacz et al., Eur. J. Pharmacol., 1993, 241, 17-25).
In addition, a number of NK-2 antagonists capable of surmounting the haemato-encephalic barrier have shown anxiolytic properties (D. M. Walsh et al., Psychopharmacology, 1995, 121, 186-191).
Cyclic compounds, and in particular cyclic hexapeptides (A. T. McKnight et al., Br. J. Pharmacol., 1991, 104, 355) and bicyclic hexapeptides (V. Pavone et al., WO 93/212227) or cyclic hexapseudopeptides (L. Quartara et al., J. Med. Chem., 1994, 37, 3630; S. L. Harbeson et al., Peptides, Chemistry and Biology, Proceedings of the Twelfth American Peptide Symposium, 1992, 124) are known in the literature for their antagonistic activity towards the NK-2 receptor of tachykinins. In EP-A-333174 linear di- and tri-peptide compounds comprising the -D-Trp-Phe-moiety are described; such compounds possess tachykinin antagonism.
It has now surprisingly been found that products of lower molecular weight, monocyclic ones, containing only four bifunctional residues linked together via peptide or pseudopeptide bond, present high pharmacological activity associated to a considerable selectivity for the human NK-2 receptor, and thus are proposed as valid alternatives.